Age-related defects in maintaining proteostasis are thought to be major contributing factors to Alzheimer's disease. This allows the build-up of toxic, amyloidogenic proteins such as phosphorylated Tau. One such defect is declining proteasome activity with age. Therefore, there is great interest in the development of agonists of the proteasome-mediated turnover of mis-folded proteins as a pharmacological strategy to treat Alzheimer?s disease, or at least delay its onset. Unfortunately, progress has been frustratingly slow and very few small molecule agonists are currently available, none of which are potent. This R21 proposal asks for support to apply both novel chemistry and an innovative screening assay to solve this problem. If successful, this project will set the stage for a chemical biology-based exploration of the utility of proteasome stimulation in combating Alzheimer?s disease.